To explore whether common genetic variation influences sJIA susceptibility, we performed a genome-wide association study (GWAS) of sJIA in collaboration with investigators from the International Childhood Arthritis Genetics Consortium (INCHARGE). INCHARGE includes investigators from major pediatric rheumatology centers in North America, South America, and Europe. The INCHARGE sJIA study population includes 988 children with sJIA and 8010 control subjects from whom we have produced a dataset of over 6.7 million genetic markers or single nucleotide polymorphisms (SNPs). To analyze this dataset, we divided the study population into 9 groups by country of origin and examined genetic associations with sJIA separately in each stratum. The association results were then meta-analyzed to identify genetic variants whose influence on sJIA disease risk transcended ethnicity. In previous reporting periods, we have established that variants of the major histocompatibility complex (MHC) locus are the strongest genetic risk factors for sJIA. Single nucleotide polymorphisms (SNPs) in the class II human leukocyte antigen (HLA) region of the MHC lead to increased risk of developing sJIA with an odds ratio of 2.6. These SNPs are in strong linkage disequilibrium with HLA-DRB1*11 alleles and reside on the class II HLA haplotype of HLA-DRB1*11/HLA-DQA1*05/HLA-DQB1*03. In the current reporting period, we have completed and published our analysis of the full GWAS dataset, which has identified 21 novel sJIA candidate susceptibility loci (less than 1 times 10 to the negative 5), the strongest of which was a susceptibility locus in a non-coding region of chromosome 1. We also identified several important susceptibility loci that may immediately nominate novel therapeutic strategies. Importantly, none of the sJIA susceptibility genes identified in our study is known to influence susceptibility to any other form of JIA or to other rheumatic diseases. Given that this was the first characterization of sJIAs genetic architecture, we performed formal statistical comparisons of the genetic underpinnings of sJIA and other JIA subtypes. These analyses demonstrated that the genetic architecture of sJIA is unique and distinct from those of oligoarticular JIA, rheumatoid factor-negative polyarticular JIA, and rheumatoid factor-positive polyarticular JIA. Based on the unique inflammatory phenotype of sJIA, combined with a complete divergence of the sJIA genetic architecture from those of the other forms of JIA, we suggest that the classification of this condition be reconsidered. Moreover, the exploration of novel therapeutic strategies for this condition should be undertaken independently of other forms of JIA and based on our pathophysiologic knowledge of sJIA. A manuscript describing these results was published in Annals of the Rheumatic Diseases. Beyond the GWAS, we are continuing to examine the role that host genetics plays in the pathogenesis and pathophysiology of sJIA. First, in collaboration with the INCHARGE and the Juvenile Arthritis Consortium for Immunochip we are performing an Immunochip study of sJIA. The goal of this study is to identify new sJIA susceptibility loci by intensively evaluating genetic variation at over 200 immunologically important loci in a large case-control collection that includes 889 sJIA cases and 16,114 health subjects. Preliminary analyses of this dataset have identified a novel sJIA susceptibility locus and we are currently performing follow-up investigations. Second, we are using targeted deep resequencing to evaluate whether rare genetic variants of sJIA candidate genes influence disease risk. The candidate genes are divided into 3 main groups: genes that showed at least a modest association with sJIA in our GWAS; genes known to cause monogenic autoinflammatory syndromes, which are phenotypically similar to sJIA; and genes known to cause familial forms of hemophagocytic lymphohistiocytosis, a condition that frequently develops in sJIA patients. Early examinations of these three datasets have produced intriguing preliminary results, and we are currently refining the analytic methods and performing follow-up investigations. Finally, we are launching our natural history protocol of sJIA to facilitate the use of contemporary genomic sequencing approaches for the evaluation of patients and families with sJIA and related inflammatory conditions. In addition to sJIA, we have studied several other inflammatory phenotypes. Together with investigators from NHGRI, NIAMS and Istanbul University, we examined the genetic basis of a large consanguineous family with early-onset systemic lupus erythematosus (SLE). Using a combination of whole exome sequencing and dye terminator sequencing, we identified a novel, homozygous loss of function mutation of the C1R gene in each affected family member. The C1R gene encodes a subunit of the complement C1 protein, and subjects bearing this truncating mutation demonstrated low serum levels of C1r and C1s, as well as strikingly low levels of total complement activity. Evaluation of human leukocyte antigen (HLA) alleles and single nucleotide polymorphism data failed to identify any SLE-associated HLA alleles or SLE risk variants that segregated within the affected family members. The results of this study were published in Arthritis & Rheumatology. Finally, we have continued to investigate the genetic basis of Behcets disease (BD), attempting to elucidate the mechanism(s) through which its strongest risk factor, HLA-B*51, influences disease risk. To evaluate whether HLA-B*51 influences BD risk through interaction with its binding partners, the killer immunoglobulin-like receptor (KIR) ligands, we examined KIR3DL1/KIR3DS1 genotypes in 1709 BD cases and 1799 healthy controls. Although we found that HLA-B*51 in BD patients did not correlate with KIR3DL1/KIR3DS1 genotypes, we unexpectedly identified an HLA-B*51-independent role for KIR3DS1 alleles in the ocular manifestations of BD. We published these findings in Genes & Immunity. To look beyond HLA-B*51, we collaborated with investigators from Turkey, Japan and NHGRIs Inflammatory Disease Section to examine whether genetic variation within genes of known immunologic importance influenced BD risk. In addition to confirming many of the genetic risk factors for BD that we have previously identified, this study identified 4 novel BD susceptibility loci (IL1A-IL1B, IL12A, IRF8 and CEBPB-PTPN1) as well as 20 other loci with evidence suggestive of association with BD. When considered together with previously identified BD risk loci, these new findings reveal substantial shared genetic architecture between BD and both inflammatory bowel disease and leprosy. Collectively, these risk factors implicate mucosal barrier function and host response to pathogens in BD. This study was published in Nature Genetics.